@article{5de52be149404b8fb7b626f8ccfc2507,
title = "Latent human herpesvirus 6 is reactivated in CAR T cells",
abstract = "Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6)1. Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4+ T cells. Using single-cell sequencing, we identify a rare population of HHV-6 {\textquoteleft}super-expressors{\textquoteright} (about 1 in 300–10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration2 or are in clinical studies3–5, we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials1,6–8 and may influence the design and production of autologous and allogeneic cell therapies.",
author = "Lareau, {Caleb A.} and Yajie Yin and Katie Maurer and Sandor, {Katalin D.} and Bence Daniel and Garima Yagnik and Jos{\'e} Pe{\~n}a and Crawford, {Jeremy Chase} and Spanjaart, {Anne M.} and Gutierrez, {Jacob C.} and Haradhvala, {Nicholas J.} and Riberdy, {Janice M.} and Tsion Abay and Stickels, {Robert R.} and Verboon, {Jeffrey M.} and Vincent Liu and Buquicchio, {Frank A.} and Fangyi Wang and Jackson Southard and Ren Song and Wenjing Li and Aastha Shrestha and Laxmi Parida and Gad Getz and Maus, {Marcela V.} and Shuqiang Li and Alison Moore and Roberts, {Zachary J.} and Ludwig, {Leif S.} and Talleur, {Aimee C.} and Thomas, {Paul G.} and Houman Dehghani and Thomas Pertel and Anshul Kundaje and Stephen Gottschalk and Roth, {Theodore L.} and Kersten, {Marie J.} and Wu, {Catherine J.} and Majzner, {Robbie G.} and Satpathy, {Ansuman T.}",
note = "Funding Information: We thank members of the laboratory of A.T.S. for helpful discussions; M. Green and G. Syal for assistance with public sequencing data; and S. Schell for assistance with clinical samples at St. Jude. C.A.L. is supported by a Stanford Science Fellowship, a Parker Institute for Cancer Immunotherapy Scholarship, a seed award from the Center for Human Systems Immunology and NIH K99 HG012076. A.T.S. is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists, the Parker Institute for Cancer Immunotherapy, a Pew-Stewart Scholars for Cancer Research Award, a Cancer Research Institute Lloyd J. Old STAR Award and a Baxter Foundation Faculty Scholar Award. S.L. is supported by the NCI Research Specialist Award (R50CA251956). This work was supported by a sponsored research agreement with Allogene Therapeutics. Part of the analysis was carried out by the Center for Translational Immunology and Immunotherapy (CeTI), which is supported by St. Jude Children{\textquoteright}s Research Hospital. 2 Funding Information: We thank members of the laboratory of A.T.S. for helpful discussions; M. Green and G. Syal for assistance with public sequencing data; and S. Schell for assistance with clinical samples at St. Jude. C.A.L. is supported by a Stanford Science Fellowship, a Parker Institute for Cancer Immunotherapy Scholarship, a seed award from the Center for Human Systems Immunology and NIH K99 HG012076. A.T.S. is supported by the Burroughs Wellcome Fund Career Award for Medical Scientists, the Parker Institute for Cancer Immunotherapy, a Pew-Stewart Scholars for Cancer Research Award, a Cancer Research Institute Lloyd J. Old STAR Award and a Baxter Foundation Faculty Scholar Award. S.L. is supported by the NCI Research Specialist Award (R50CA251956). This work was supported by a sponsored research agreement with Allogene Therapeutics. Part of the analysis was carried out by the Center for Translational Immunology and Immunotherapy (CeTI2), which is supported by St. Jude Children{\textquoteright}s Research Hospital. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2023",
month = nov,
day = "16",
doi = "https://doi.org/10.1038/s41586-023-06704-2",
language = "English",
volume = "623",
pages = "608--615",
journal = "NATURE",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7987",
}